Epilepsy is a family of debilitating neurological disorders that afflicts approximately 4% of the population. The disease often begins in childhood and persists throughout the lifetime of the patient. Although a number of anti-convulsive therapies have been developed for the control of epilepsy, seizures remain uncontrolled in approximately one-third of patients with epilepsy, and treatment failures are common (Loscher, W. and Schmidt, D., 2002, Epilepsy Res. 50:3–16).
Accordingly, physicians, scientists and research-based organizations interested in the control and prevention of epilepsy have repeatedly stressed the need for new, clinically correlated animal models with which to study the aetiology of these disorders, and to evaluate potential new therapeutants and therapeutic strategies.
To date, rodent models of epilepsy are restricted to either (a) chemically or electrically—induced acute status epilepticus, (b) spontaneous seizures following chemical or electrical kindling, or (c) genetic models, such as inbred rodent strains that manifest a reduced seizure threshold (Cole, A. J., Koh, S. and Zheng, Y., In: T. Sutula and A. Pikanen (eds.). Progress in Brain Research, 2002, 135:13–23). However, genetic models are also characterized by chronic systemic disease that limits their utility.
For instance, U.S. Pat. No. 5,698,766 discloses a transgenic mouse model lacking 5HT2C receptors. While it is proposed that this animal model is useful for testing drugs against diseases that result in seizures, such as epilepsy, such animals are also overweight due to abnormal feeding behaviour, and are prone to spontaneous death from seizures.
Another transgenic mouse model is described in U.S. Patent Application Publication No. U.S. 2002/0104107 A1, which involves transgenic mice expressing a hypersensitive nicotinic acetylcholine receptor. Although these mice have been proposed as a model system for studying agents that modulate seizures associated with epilepsy, they are primarily useful for examining and manipulating neurobehaviours mediated by nicotine.
Other non-transgenic rodent models have been produced through treatment of the rodent with a neurotoxin. For example, U.S. Pat. No. 5,549,884 discloses a non-transgenic animal produced by inducing brain lesions in the ventral hippocampus of prepubescent rats or mice, by injecting a neurotoxin such as kainic acid into the brain. Once the animal reaches puberty, abnormal behaviour and biological phenomena associated with schizophrenia emerge.
At present, the best animal models available for the study of epilepsy involve acute neurotoxic insults to the mature animal (commonly rats). These models produce motor seizures, changes in cortical EEGs, and neuroanatomical features that approximate human TLE (Ben-Ari, Y. and Cossart, R., Trend. Neurosci. [2000] 23:580–587). Epilepsy, however, often appears to have a developmental history beginning in childhood, and is by definition a chronic disease, or at least a disease that manifests itself over a period of time, not simply as a response to an acute insult (Cole, A. J., et al. In: T. Sutula and A. Pikanen (eds.) Progress in Brain Research [2002] 135:13–23).
Administration of acute high doses of kainic acid, a known kainic acid receptor agonist, has been shown to produce immediate seizures in infant or young rats, but does not cause lasting behavioural, neurochemical, and neuroanatomical correlates of seizure disorders (Stafstrom, C. E., et al., Epilepsia [1993] 34:420–432, Stafstrom, C. E., et al., Brain Res. Dev Brain Res. [1992] 65:227–236, and Sperber, E. F., et al., Brain Res. Dev Brain Res. [1991] 60:88–93). As well, existing chronic models of epilepsy both display and require status epilepticus, causing high mortality, and often underrepresent the complexity of seizure disorders and hence are not always predictive of the clinical profile of many epileptic patients (Loscher, W., Epilepsy Res. [2002] 50:105–123). Thus, existing animal models do not adequately model typical human epilepsy (Cole, A. J., et al., In: T. Sutula and A. Pikanen [eds.] Progress in Brain Research [2002] 135:13–23). Moreover, new animal models that simulate chronic brain dysfunction have been identified as one of the most important prerequisites for advancing epilepsy research (Loscher, W. and Schmidt, D. Epilepsy Res. [2002] 50:3–16).
Therefore, it is recognized that advancing research in epilepsy, and particularly idiopathic epilepsy, requires a developmental animal model; the genesis of which does not rely on an acute traumatic event. The present invention aims to solve this problem by providing a new developmental animal model of temporal lobe epilepsy.